Adenovirus (Ad) mediated gene transfer is a promising technology for the treatment of many genetic disorders of the Central Nervous System (CNS). Many of the drawbacks that exist with first-generation Ad vectors have been resolved through the use of 'gutted'or 'helper-dependent'vectors. The genetic basis of neurodegeneration is currently best understood in the retina. In addition, relative to the rest of the CNS, the physical accessibility of the eye makes the retina an excellent model system for studying gene therapy for the CNS. Upon ocular delivery, Ad vectors primarily infect the retinal pigment epithelium (RPE) and the Mueller cells of the retina. However, the diseases that most frequently cause blindness are associated with the expression of mutant proteins in the photoreceptor neurons. In our preliminary studies we have found that adenovirus-delivered green fluorescent protein fused to the full length Herpes Simplex Virus (HSV) tegument protein VP22 can translocate from infected cells to uninfected cells in culture or from the RPE to photoreceptors in vivo. This has led to the hypothesis we wish to test in this study: Can HSV VP22 be used to deliver therapeutic proteins to photoreceptor neurons via the RPE? This will be answered using a mouse model of inherited retinal degeneration (rd). Specifically, in this study we propose to 1) Construct an adenovirus vector expressing the protein transduction domains (PTD) of HSV VP22 fused to GFP and compare their ability to traffic GFP in cell culture and in murine retina. 2) Construct an adenovirus vector expressing a fusion between beta PDE and the PTD of HSV VP22. Assess the ability of this virus to express a functional PDE. 3) Administer a gutted adenovirus vector expressing either a VP22-beta PDE fusion to the retina of rd mice (which have a naturally occurring mutation in beta PDE) and assess the effects upon photoreceptor degeneration.